2,3-Dihydro-5-alkoxy-5-phenyl-5H-imidazo[2,1-a]isoindoles

ABSTRACT

Novel 2[2-(1,3-diazacycloalk-2-enyl)]benzophenone compounds and novel 1,3-diazacycloalkenyl[2,1-a]isoindole compounds having useful analgesic and psychostimulant properties are prepared inter alia by condensation of o-benzoylbenzaldehydes with aliphatic diamines.

RELATED APPLICATIONS

This is a division of application Ser. No. 639,315 filed May 18, 1967,which in turn is a continuation-in-part of U.S. Patent application Ser.No. 626,965, filed Mar. 30, 1967.

BRIEF SUMMARY OF THE INVENTION

This invention relates to a novel class of2[2-(1,3-diazacycloalk-2-enyl)]benzophenones and novel1,3-diazacycloalkenyl[2,1-a]isoindoles, novel processes andintermediates for the preparation of said novel products and derivativesthereof and to the use of said novel compounds as pharmaceuticals. Moreparticularly, the invention in its product aspect relates to novelcompounds of the formula ##SPC1##

Wherein B represents an alkylene chain of 2 to 4 carbon atoms in whichone or more of the hydrogens can be replaced by lower alkyl; and R₁, R₂,R₃ and R₄ are each independently selected from the group consisting ofhydrogen, halogen, lower alkyl, lower alkoxy, hydroxy andtrifluoromethyl

And pharmaceutically acceptable acid addition salts thereof.

Compounds of formula I can undergo a prototropic shift to form compoundsof the formula ##SPC2##

Wherein R₁, R₂, R₃, R₄ and B each have the same meaning as hereinabove.

The invention includes both tautomeric isomers as well as mixturesthereof. Tautomeric mixtures can be represented schematically as##SPC3##

Wherein R₁, R₂, R₃, R₄ and B each have the same meaning as hereinabove.

DETAILED DESCRIPTION

In one product aspect this application pertains to the novel compoundsof formulas I and II and derivatives thereof. Of particular interest arethe compounds of formulas I and II wherein B represents the group##EQU1## and R₅ and R₆ are each independently hydrogen or lower alkyl,i.e., compounds of the formulas ##SPC4##

Wherein R₁, R₂, R₃ and R₄ each have the same meaning as hereinabove; andR₅ and R₆ are each independently hydrogen or lower alkyl

And their pharmaceutically acceptable acid addition salts and tautomericmixtures.

Compounds of formulas I-a and II-a wherein R₁, R₃, R₅ and R₆ are eachhydrogen, i.e., compounds of the formulas ##SPC5##

Wherein R₂ and R₄ each have the same meaning as hereinabove

And their pharmaceutically acceptable acid addition salts and tautomericmixtures constitute a preferred group.

In another product aspect this application pertains to the mixed ethersobtained from compounds of formula II and lower alkanols, i.e.,compounds of the formula ##SPC6##

Wherein R₁, R₂, R₃, R₄ and B each have the same meaning as hereinabove;and R₇ is lower alkyl.

In still another product aspect this application pertains to novelintermediates which will be more fully described with reference to theseveral processes for the preparation of compounds of formulas I and II.

In one of its process aspects this application pertains to thepreparation of compounds of formulas I, II and II-d according to thefollowing reaction sequence. ##SPC7##

wherein R₁, R₂, R₃, R₄, R₇ and B each have the same meaning ashereinabove.

The diol starting materials of formula V are known compounds or arereadily obtainable in analogy to the preparation of the known compounds.The diol starting materials can be readily converted to the dicarbonylintermediates of formula IV by oxidation techniques which are known perse such as, for example, using selenium dioxide and the like, as theoxidizing agent or by employing other oxidizing systems such as chromiumtrioxide in pyridine.

Treatment with an oxidizing agent can be conveniently carried out in anorganic solvent such as, for example, dimethylformamide,dimethylsulfoxide; hydrocarbon solvents such as benzene, toluene;alkanols, e.g., the lower alkanols, methanol, ethanol, etc.; acetic acidand the like. The oxidation reaction is preferably carried out at anelevated temperature suitably at a temperature between about roomtemperature and about 150°C.

The intermediates of formula IV are themselves novel compounds and thusalso constitute part of this invention. The intermediates of formula IVare readily condensed with diamines of the formula

    NH.sub.2 --B--NH.sub.2                                     XII

wherein B has the same meaning as hereinabove

by mixing the components or by reacting them in the presence of anorganic solvent such as benzene, toluene; alcohols such as loweralkanols and the like. The condensation is conveniently carried out atroom temperature or above, preferably at a temperature between about20°C. and 150°C. Alternatively, the diamine reactant of formula XII canbe employed as a salt thereof in which case the reaction is conducted byheating the mixture of reactants to a melt.

The reaction products, i.e., the compounds of formula III, can bereadily oxidized, for example, by treatment with an oxidizing agent suchas hydrogen peroxide or by exposure to gaseous oxygen at roomtemperature to give the peroxides of formula II-c which are readilyreduced to the corresponding end products. The oxidation is convenientlycarried out in an organic solvent such as alcohols, dimethylformamide,etc. at room temperature. Higher or lower temperatures, e.g., betweenabout 20°C. and 100°C., can also be employed.

Since the peroxide intermediates readily undergo reduction, the reactionmixture obtained upon treatment of a compound of formula III with anoxidizing agent will ordinarily contain the end products along with theperoxide intermediate of formula II-c. Complete reduction of theperoxide can be accomplished without separating it from the reactionmixture and, in a preferred embodiment, the oxidation product issubmitting directly to treatment with a reducing agent. If desired,however, the peroxide intermediate of formula II-c can be separated fromthe reaction mixture obtained upon treatment of a compound of formulaIII with an oxidizing agent by any of the usual techniques, e.g.,chromatographic separation, fractional crystallization, etc.

The reduction of the peroxide is conveniently carried out by employingany reducing agent conventionally used for the reduction of peroxidessuch as sodium sulfite, trialkylphosphite, etc. preferably in thepresence of an organic solvent such as an alcohol, e.g., methanol,ethanol, etc.; dimethylformamide and the like, or when using a salt ofthe peroxide, the reduction can be carried out in an aqueous solvent,e.g., in an aqueous alcoholic solvent. The reduction is suitably carriedout at room temperature or above, preferably at a temperature betweenabout 20°C. and 100°C.

As noted above, the hydroxyl proton of a compound of formula II canundergo a prototropic shift to form the corresponding isomeric endproduct of formula I. In solution the product obtained upon oxidationand reduction of an intermediate of formula III will ordinarily be amixture of the tautomeric forms I and II. The relative amounts of theisomeric forms present is dependent upon such factors as the solventsystem employed, the pH of the medium and the particular product, i.e.,the meaning of B, R₁, R₂, R₃ and R₄ in formulas I and II. For example,in a solution of chloroform the product obtained upon oxidation andreduction of 2,3-dihydro-5-phenyl-5H-imidazo[2,1-a]isoindole contains amixture of the isomers2,3-dihydro-5-hydroxy-5-phenyl-5H-imidazo[2,1-a]isoindole and2-(2-benzoylphenyl)-2-imidazoline in a ratio of about 1:1. The acidaddition salts isolated in the ordinary manner from the reaction productof the oxidation and reduction of2,3-dihydro-5-phenyl-5H-imidazo[2,1-a]isoindole are ordinarily obtainedas structure I.

Compounds of formula II-d are prepared from the compounds of formula IIby treating an acid addition salt, e.g., the hydrochloride, hydrobromideor the like, of a formula II compound with a lower alkanol preferably atan elevated temperature. The etherification can be suitably carried outusing the lower alkanol as solvent or in the presence of an inertorganic solvent such as ether and the like and preferably at atemperature between about room temperature and the reflux temperature ofthe reaction mixture, i.e., up to about 150°C.

The novel compounds of formula II-d as well as the intermediates offormulas II-c and III are obtained as racemates. It is intended toinclude in this invention all of the stereoisomeric forms whether theyare obtained as racemic mixtures or as the separated optically activeantipodes.

The intermediates of formulas III and II-c are also novel compoundswhich constitute part of this invention. Compounds of formula III are,in addition to being useful as intermediates in the preparation ofcompounds of formulas I and II, also useful as psychostimulant,anti-inflammatory and anti-pyretic agents.

Alternatively, the compounds of formulas III, II and I can be preparedaccording to the following reaction scheme: ##SPC8##

wherein R₁, R₂, R₃, R₄ and B each have the same meaning as hereinabove.

According to one alternative synthesis outlined above the intermediatesof formula III are prepared by cyclization of a phthalimidine of formulaVI. The cyclization of a phthalimidine of formula VI to form anintermediate of formula III is readily accomplished by treatment with aLewis acid such as titanium chloride, boron trifluoride and the like.The oxidation and reduction of the formula II intermediates to form thedesired end products is accomplished by the procedures described above.

The reaction with Lewis acid is preferably carried out in the presenceof an inert organic solvent, e.g., hydrocarbon solvents such as toluene,xylene and the like, and preferably at an elevated temperature suitablyat the reflux temperature of the solvent employed. A preferredtemperature range for the cyclization of the phthalimidines is atemperature between about 50°C to about 200°C. The phthalimidineintermediates of formula VI are prepared by condensing a3-phenylphthalide of formula VII with a diamine of formula XII. The3-phenylphthalides of formula VII and the diamines of formula X employedas starting materials are known compounds or analogs of known compoundswhich are readily accessible in analogy to the known compounds.

The preparation of the formula VI intermediates is catalyzed by salts oforganic bases such as pyridine, trialkylamine, quinoline,ethylenediamine, etc., with acids such as an organic acid, a mineralacid, e.g., sulfuric acid, hydrohalic acid, phosphoric acid, perchloricacid, etc., or a Lewis acid such as zinc chloride, aluminum chloride,etc. Preferred catalysts for the reaction are the salts ofethylenediamine and pyridine such as pyridinium hydrochloride and thelike. It is preferred to carry out the reaction with an excess of theethylenediamine reactant as solvent. However, inert organic solventssuch as alcohols, e.g., methanol, ethanol, etc.; hydrocarbons, e.g.,benzene, toluene, etc.; ethers, e.g., tetrahydrofuran, dioxane, etc.,can also be employed. The reaction is carried out at an elevatedtemperature, preferably at a temperature about 100°C. Especiallysuitable temperatures for carrying out this reaction are temperaturesbetween about 180°C. and about 250°C.

The preparation of the phthalimidines of formula VI does not itselfconstitute part of this invention and is given here for the sake ofcompleteness only.

Alternatively, the intermediates of formula III can be prepared from thecorresponding diazacycloalkenylisoindolones of formula VIII by reactionwith an appropriate phenyl-organometallic derivative of the formula##SPC9##

wherein R₃ and R₄ each have the same meaning as hereinabove; and Z isLi, MgBr, MgI, MgCl or the like.

The reaction with a phenyl-lithium derivative of formula XI can beconveniently carried out in the presence of an inert solvent at aboutroom temperature. Higher or lower temperatures suitably in the range ofabout 10°C. to about 100°C. can also be employed. Suitable solvents thatcan be utilized are, for example, the hydrocarbons such as benzene,toluene, xylene, etc., ethers, and the like or mixtures of eachsolvents.

The diazacycloalkenylisoindolone intermediates of formula VIII are alsonovel compounds and thus constitute a part of this invention. They arereadily prepared by the condensation of a phthalaldehydic acidderivative of formula IX with an alkylene diamine of formula XII. Thecondensation reaction is conveniently carried out in the presence of aninert organic solvent and preferably at an elevated temperature.Suitable temperatures for carrying out the condensation reaction aretemperatures between about 20°C. and about 100°C. or the boiling pointof the reaction mixture. As solvent for the condensation there can besuitably employed any of the usual organic solvents such as alcohols,hydrocarbons, ethers, etc.

The phthalaldehydic acid derivatives of formula IX are known startingmaterials or analogs of known compounds readily obtained by knownprocesses.

In still another alternative process, the end products of formula I canbe obtained by oxidation of a 1-phenyl-2-aminoalkylisoindolinederivative as outlined below: ##SPC10##

wherein B, R₁, R₂, R₃ and R₄ are as defined hereinabove; and X ishalogen, preferably chlorine, iodine or bromine or other similar leavinggroups such as mesyloxy, tosyloxy and the like.

The oxidation is accomplished by treating with an oxidizing agent suchas gaseous oxygen or chemical oxidants such as chromium trioxide inacetic acid and the like.

The reaction is preferably carried out in the presence of an organicsolvent such as, for example, hydrocarbon solvents, e.g., benzene,toluene or the like; alkanoic acids, e.g., acetic acid, propionic acid,etc.; ethers, alcohols and solvents such as dimethylformamide, etc. Thereaction can be suitably accomplished at room temperature or at anelevated temperature, preferably at a temperature between about 20°C.and 100°C. The 1-phenyl-2-aminoalkylisoindoline intermediates areprepared from the diols of formula V via a diester of formula V-a. Thediesters are obtained by the usual techniques for esterification, e.g.,treating the diol with one of the ordinary esterifying agents such as ahalo acid and halides such as phosphorous halide, thionyl halide, tosylhalide, etc. The diester of formula V-a is in turn converted to the1-phenyl-2-aminoalkylisoindoline intermediate of formula VI bycondensing with a diamine of formula XII.

The reaction with diamine is conveniently carried out by adding thediester of formula V-a to the diamine at room temperature. Preferably,there is employed a large molar excess of diamine. The reaction can alsobe carried out at temperatures above or below room temperature, althoughfor practical reasons it is preferred to operate at a temperaturebetween about 0°C. and 100°C. The reaction is suitably carried out inthe presence of an organic solvent such as, for example, benzene,methylene chloride, ether, tetrahydrofuran and the like; or, in the casewhere either or both of the reactants are liquid under the conditionsemployed in the reaction, the reaction is conveniently carried out inthe absence of a solvent.

The preparation of the 1-phenyl-2-aminoalkylisoindolines of formula VIdoes not constitute part of this invention and is given here for thesake of completeness only.

As used throughout this application the term "lower alkyl" denotesstraight and branched chain hydrocarbons containing 1 to 6 carbon atomssuch as methyl, ethyl, propyl, isopropyl, butyl, sec.-butyl, t.-butyland the like. The term "lower alkoxy" denotes lower alkylether groupswherein the alkyl group is as defined above. The term "halogen" as usedherein includes all four halogens, i.e., chlorine, bromine, iodine andfluorine.

Suitable salts of the compounds of formula I are prepared from nontoxicorganic and inorganic acids. Suitable organic acids are, for example,maleic acid, fumaric acid, ascorbic acid, tartaric acid, salicylic acid,succinic acid, citric acid and the like. Suitable inorganic acids are,for example, the hydrohalic acids, e.g., hydrochloric acid andhydrobromic acid; sulfuric acid, sulfamic acid, phosphoric acid, etc.The acid addition salts are readily prepared by the usual techniques forthe preparation of acid addition salts which are readily apparent tothose skilled in the art.

As has been indicated hereinabove the novel end products of thisinvention, i.e., the compounds of the formula I and theirpharmaceutically acceptable acid addition salts and the compounds offormula II-d and their pharmaceutically acceptable acid addition salts,are useful as psychostimulants. When administered, for example, orally,to animals such as mice they produce a direct-acting stimulant effect oflong duration in single doses in amounts ranging from 0.03 mg/kg to 50mg/kg. By way of illustration the compound of Example 10,2-(2-benzoylphenyl)-2-imidazoline, which has an LD₅₀ in mice of 200mg/kg p.o.; 130 mg/kg s.c.; 77 mg/kg i.p.; and 37 mg/kg i.v. (Proc. Soc.Exptl. Biol. Med., Vol. 57, page 261); reversed the hypothermia inducedby reserpine in mice at a dose of 10 mg/kg s.c. (Med. Pharmacol. Exp.,Vol. 12, pages 226-232, 1965); prevented the ptosis induced bytetrabenazene in mice at .06 mg/kg p.o. (Pletscher et al., Progress.Drug Research, Vol. II, page 417, 1960 ); reversed the reserpine (10mg/kg s.c.) induced sedation in mice by increasing their locomotoractivity at doses of 25-50 mg/kg p.o. (Med. Pharmacol. Exp., Vol. 12,pages 226-232, 1965); and potentiated the effects ofβ-(3,4-dihydroxyphenyl)-α-alanine (DOPA) in mice at a dose of 6.25 mg/kgi.p. (Arc. Exp. Path. and Pharm., Vol. 140, page 237). The compounds ofthis invention have psychostimulant effects qualitatively similar inmany respects to those of imipramine and amphetamine which are wellknown for their therapeutic uses and properties. Among otherillustrative compounds of formulas I and II-d which have been similarlytested and found to be qualitatively similar to2-(2-benzoylphenyl)-2-imidazoline, there can be named by way ofexemplification the following:

5-(4-chlorophenyl)-2,3-dihydro-5-hydroxy-5H-imidazo[2,1-a]isoindole;

2,3-dihydro-5-hydroxy-5-(4-methoxyphenyl)-5H-imidazo[2,1-a]-isoindole;and

2,3-dihydro-5-methoxy-5-phenyl-5H-imidazo[2,1-a]isoindole.

The activity of the claimed compounds of formulas I and II-d firstdemonstrated by pharmacological evaluation in warm-blooded animals asindicated herein permits their use in therapy in the same general manneras imipramine or amphetamine, which latter compounds exhibitpsychostimulant activity in the DOPA potentiation test at doses of 10mg/kg i.p. and 1.0 mg/kg i.p. respectively and in the ptosis preventiontest at doses of >60 mg/kg and 7.5 mg/kg respectively. As a furtherillustration of the psychostimulant activity of the compounds offormulas I and II-d, the compound of Example 21,2,3,4,5-tetrahydro-7-hydroxy-7-phenyl-7H-diazepino[2,1-a]isoindole,which has an LD₅₀ of 40 mg/kg i.v., prevented the ptosis induced bytetrabenazene at 0.4 mg/kg p.o.; reversed the hypothermia andhypometabolic effects induced by reserpine (10 mg/kg s.c.) in mice at 25mg/kg p.o.; and potentiated the effects of DOPA in mice at a dose of 7.5mg/kg i.p. The compounds of this invention thus demonstrate a pattern ofactivity associated with anti-depressants of known clinical efficacy andare similarly useful as psychostimulants in the treatment of depressedstates, for example, in cases of simple depression or in cases ofchronic nervous exhaustion.

In addition to their use as psychostimulants, the compounds of formulasI and II-d are also useful as analgesic agents. By way of example,2-(2-benzoylphenyl)-2-imidazoline, when submitted to standardpharmacological tests for analgesic properties, exhibited markedactivity in the writhing test in mice at doses of 30.8 mg/kg p.o. and 5mg/kg s.c. and anti-pyretic activity in rats at doses of 6.25 to 50mg/kg p.o. The compound also showed potent anti-inflammatory activity inthe inflamed rat foot test at 6.25 mg/kg p.o. and anti-edema activity inthe Carrageenan anti-edema rat paw test at 6.25 mg/kg p.o. In theunanesthetized cat test for muscle relaxants the compound was active ata dose of 2.5 mg/kg p.o. Based on the foregoing pharmacological tests inanimals, the analgesic properties of the novel end products of thisinvention and particularly those of 2-(2-benzoylphenyl)-2-imidazolinecan be likened to the analgesic properties of phenylbutazone which iswell known for its therapeutic uses and properties. Compounds offormulas I and II-d are also useful as anorexigenic agents owing totheir marked activity in the 4-hour anti-obesity test in rats whereincompounds of this class have demonstrated activity qualitatively similarto amphetamine. Compounds of this series have also demonstrated usefulcardiovascular properties. For example,2-(2-benzoylphenyl)-2-imidazoline in dogs at 4 mg/kg i.v. produced anincrease in blood pressure of 10 mm. Hg after 2 minutes followed bygradual increase to 25 mm. Hg.

Compounds of formula I have also been found to be active as anti-fungalagents. For example, they have been found to be active in vitro inCandida albicans, Microsporum audouini and Trichophyton mentagrophytes.Accordingly, these compounds can be employed as anti-fungal agents inthe treatment of pathogenic diseases caused by these organisms. Theycan, for example, be employed in the treatment of infectious fungaldiseases such as moniliasis and dermatomycoses. For the treatment offungal infections the compounds of formula I can be employed by applyinga suitable composition containing about 0.1 mg. to about 5 g. of activematerial over the site of the infection. Suitable compositions areprepared by embodying a compound of formula I or a pharmaceuticallyacceptable salt thereof in a conventional carrier suitable for topicaladministration.

The novel end products of this invention, i.e., the compounds offormulas I and II-d are mostly white crystalline odorless solids meltingat temperatures in the order of 200°C. They have basic properties andcan be conveniently prepared in the form of their acid addition salts.Suitable salts are prepared as described hereinabove. The salts arecharacteristically white crystalline odorless solids soluble in waterand have good stability under ordinary conditions.

The compounds of formulas I and II-d, preferably in the form of theiracid addition salts can be formulated into preparations suitable foradministration by enteral or parenteral routes. They can be embodied inpharmaceutical unit dosage forms containing from about 0.5 mg. to about100 mg. of active material, i.e., a compound of formulas I or II-d or asalt thereof. Parenteral formulations will ordinarily contain less ofthe active substance than compositions intended for enteral, e.g., oral,administration. For oral administration the products of this inventioncan be prepared as tablets, capsules and the like containing about 10 to50 mg. of active material. Formulations suitable for oral administrationmay be such as to provide either immediate, or in the alternative,sustained release of the active drug. In general, the formulations willbe prepared with pharmaceutically acceptable adjuvant materialscomprising from about 60 to about 98 per cent of the weight of thecompositions in oral dosage form.

For parenteral administration the compounds can be formulated with aliquid diluent, for example, distilled water, in the preparation of asuitable parenteral dosage form. The preferred parenteral dosage formwill contain from about 0.5 mg. to about 15 mg. of the active drug. Ingeneral, the compounds of this invention are formulated withconventional inert adjuvants into dosage forms suitable for enteral orparenteral administration following the conventional techniques andprocedures of the prior art. Suitable dosage forms include tablets andcapsules as well as solutions, emulsions and suspensions. The inertadjuvants which are suitable for use in preparing the various dosageforms include liquids and solids inorganic or organic in nature such aswater, gelatin, lactose, starch, magnesium stearate, talc, vegetableoils, gums polyalkylene glycols, Vaseline, etc. Additionally, thecompounds can be used in combination with preservatives, stabilizers,wetting or emulsifying agents, salts for altering the osmotic pressure,buffers, etc. If desired, the compounds can be used also in admixturewith other therapeutically valuable substances. Specific embodimentsshowing illustrative formulations of an exemplary compound of formula Ifollow.

    ______________________________________                                        Tablet Formulation                                                                                     Per Tablet                                           ______________________________________                                        2-(2-benzoylphenyl)-2-         10.0 mg.                                       imidazoline                                                                   Lactose                        113.5 mg.                                      Corn Starch                    70.5 mg.                                       Pregelatinized Corn Starch     8.0 mg.                                        Calcium Stearate               3.0 mg.                                                        Total Weight   205.0 mg.                                      ______________________________________                                    

Procedure:

1. 2-(2-Benzoylphenyl)-2-imidazoline was mixed with the lactose, cornstarch, and pregelatinized corn starch in a suitable size mixer.

2. The mix was passed through a Fitzpatrick Comminuting Machine fittedwith a No. 1A screen and with knives forward.

3. The mix was returned to the mixer and moistened with water to a thickpaste. The moist mass was passed through a No. 12 screen and the moistgranules were dried on paper-lined trays at 100°F.

4. the dried granules were returned to the mixer, the calcium stearatewas added and mixed well.

5. The granules were compressed at a tablet weight of 200 mg., usingstandard concave punches having a diameter of 5/16 inch.

    ______________________________________                                        Suppository Formulation                                                                               Per 1.3 Gram                                                                  Suppository                                           ______________________________________                                        2-(2-benzoylphenyl)-2-imidazoline                                                                       0.025 gram                                          Wecobee M (E. F. Drew Company                                                                           1.230 gram                                                522 Fifth Avenue                                                              New York, New York)                                                     Carnauba Wax              0.045 gram                                          ______________________________________                                    

Procedure:

1. The Wecobee M and the carnauba wax were melted in a suitable sizeglass-lined container (stainless steel may also be used), mixed well andcooled to 45°C.

2. 2-(2-benzoylphenyl)-2-imidazoline, which had been reduced to a finepowder with no lumps, was added and stirred until completely anduniformly dispersed.

3. The mixture was poured into suppository molds to yield suppositorieshaving an individual weight of 1.3 grams.

4. The suppositories were cooled and removed from molds. They wereindividually wrapped in wax paper for packaging. (Foil may also beused.)

    ______________________________________                                        Capsule Formulation                                                                                   Per Capsule                                           ______________________________________                                        2-(2-benzoylphenyl)-2-         25 mg.                                         imidazoline                                                                   Lactose                       158 mg.                                         Corn Starch                    37 mg.                                         Talc                           5 mg.                                                          Total Weight  255 mg.                                         ______________________________________                                    

Procedure:

1. 2-(2-Benzoylphenyl)-2-imidazoline was mixed with the lactose and cornstarch in a suitable mixer.

2. The mixture was further blended by passing through a FitzpatrickComminuting Machine with a No. 1A screen with knives forward.

3. The blended powder was returned to the mixer, the talc added andblended thoroughly. The mixture was then filled into No. 4 hard shellgelatin capsules on a Parke Davis capsulating machine (any similar typemachine may be used).

    ______________________________________                                        Parenteral Formulation                                                                                  Per cc.                                             ______________________________________                                        2-(2-benzoylphenyl)-2-imidazoline                                                                         2.5 mg.                                           Tartaric Acid  q.s. ad pH 3.0                                                 Phenol Anhydrous            4.5 mg.                                           Water for Injection, U.S.P. 1.0 cc.d                                          ______________________________________                                    

Procedure:

1. 2-(2-Benzoylphenyl)-2-imidazoline was slurried in part of the waterfor injection.

2. 2-(2-Benzoylphenyl)-2-imidazoline was solubilized by slowly addingthe tartaric acid to a pH of approximately 3.0.

3. The phenol anhydrous was then added.

4. The solution was filtered and allowed to stand for 24 hours. It wasthen filtered through an 02 Selas candle.

5. The solution was filled into desired size ampuls and sealed under anatmosphere of nitrogen.

6. All ampuls were inspected; those containing excessive amounts offibers were rejected.

The drug was prepared in duplex ampuls, one containing the dry drug andthe other containing the special diluent.

    ______________________________________                                                            Dry Fill Ampul 5 cc.                                      ______________________________________                                        2-(2-benzoylphenyl)-2-imidazoline                                                                   25 mg.                                                  ______________________________________                                    

A parenteral grade of the drug, fiber-free, was filled into the ampulusing a Diehl Mater electric filler or other suitable type filler. Theampuls were sealed and sterilized at 255°F. for 2 hours.

Immediately before use the powder was solubilized with the followingsolution:

                       Special Diluent 2 cc.                                                         per ml.                                                    ______________________________________                                        Tartaric acid        16 mg.                                                   Water for Injection  q.s. to                                                                       1.0 ml.                                                  ______________________________________                                    

In a suitable container under an atmosphere of nitrogen the tartaricacid was dissolved in part of the water for injection. The solution wasmade to volume, filtered through an 02 Selas candle filter and filledinto 2 cc. flint ampuls. The filling should be done under an atmosphereof nitrogen. The ampuls were sealed and sterilized at 212°F. for 30minutes. The ampuls were then inspected and those that leaked orcontained fibers were discarded.

The drug in the preferred oral dosage form, i.e., tablets or capsulescontaining 10 to 25 mg. of active material, will be administered underordinary circumstances three or four times daily. The parenteralcomposition will be administered ordinarily one or two times daily.Effective dosages for the administration of compounds of this invention,i.e., the compounds of formulas I and II-d, will, of course, depend inall instances upon the severity and individual characteristics of eachcase as determined by the prescribing practitioner. It will beunderstood that dosage forms containing larger and smaller quantities ofthe active drug ingredient are encompassed by the scope of thisinvention and that such dosage forms can be administered more or lessfrequently than indicated heretofore. It will be understood that dosageforms containing inert adjuvants in quantities which are greater or lessthan those indicated heretofore are also encompassed by this invention.

The invention will be more fully understood from the examples whichfollow. These examples are illustrative of the invention and are not tobe construed as limitative thereof. All melting points are in degreescentigrade. Decomposition melting points were taken in a Thomas Hooverapparatus in open capillaries. They may vary ±10° depending on the rateof heating.

EXAMPLE 1 Preparation of 2-benzoylbenzaldehyde

A mixture of 1 g. of selenium dioxide and 1 g. of2-hydroxymethylbenzhydrol in 5 ml. of acetic acid was refluxed for 41/2hours. The solution was cooled, filtered from selenium and the filtratewas poured into ice water and made alkaline with sodium hydroxide.Extraction with ether gave a yellow oil to which petroleum ether wasadded. White prisms were obtained which melted at 64°-67°. Ultravioletmaximum (2-propanol) at 226/7 mμ (ε = 15,750) and 251/2 mμ (ε = 18,500),inflexion at 294 mμ (ε = 2600); infrared absorption (CHCl₃) at 1665 cm⁻¹ and 1705 cm⁻ ¹

Anal. Calcd. for C₁₄ H₁₀ O₂ : C, 79.98; H, 4.79; Found: C, 80.00; H,4.68

EXAMPLE 2 Preparation of 2-(p-chlorobenzoyl)-benzaldehyde

A solution of 18.6 g. of 4'-chloro-2-hydroxymethylbenzhydrol in 100 ml.of acetic acid and 10.4 g. selenium dioxide was refluxed for 2 hours.The mixture was poured on ice and made alkaline and extracted withether. Concentration of the ether solution and addition of petroleumether gave pale yellow prisms which after recrystallization from amixture of ether and petroleum ether gave2-(p-chlorobenzoyl)-benzaldehyde melting at 112°-113°. Ultravioletinflexion (2-propanol) at 225 mμ (ε = 17,500) and maximum at 259 mμ (ε =22,500), infrared absorption (CHCl₃) at 1670 cm.sup.⁻¹ and 1705cm.sup.⁻¹.

Anal. Calcd. for C₁₄ H₉ ClO₂ : C, 68.72; H, 3.71; Found: C, 69.12; H,3.50

EXAMPLE 3 Preparation of 2-(p-anisoyl)-benzaldehyde

A solution of 26 g. of 4'-methoxy-2-hydroxymethylbenzhydrol in 140 ml.of acetic acid and 14.5 g. selenium dioxide was refluxed for 2 hours.The mixture was filtered and the filtrate was made basic. An oilseparated which crystallized on standing and was collected.Recrystallization from a mixture of methylene chloride and petroleumether gave off-white platelets melting at 90°-91°. Ultraviolet maxima(2-propanol) at 221 mμ (ε = 21,600), 258 mμ (ε = 12,400) and 292 mμ (ε =17,000); infrared absorption (CHCl₃) at 1660 cm.sup.⁻¹ and at 1700cm.sup.⁻¹.

Anal. Calcd. for C₁₅ H₁₂ O₃ : C, 74.99; H, 5.03; Found: C, 75.27; H,5.26

EXAMPLE 4 Preparation of 2-benzoyl-4-chlorobenzaldehyde

A solution of 9.3 g. of 5-chloro-2-hydroxymethylbenzhydrol in 50 ml. ofacetic acid and 5.2 g. of selenium dioxide was refluxed for 3 hours. Themixture was filtered, cooled, poured on ice, made alkaline and extractedwith ether. Concentration and addition of petroleum ether gave theproduct as prisms which after recrystallization from a mixture of etherand petroleum ether melted at 82°-84°. Ultraviolet maxima (2-propanol)at 230 mμ (ε = 19,500) and 257 mμ (ε = 23,500); infrared absorption(CHCl₃) at 1675 cm.sup.⁻¹ and 1705 cm.sup.⁻¹.

Anal. Calcd. for C₁₄ H₉ ClO₂ : C, 68.72; H, 3.71 Found: C, 69.05; H,3.87

EXAMPLE 5 Preparation of 2-(4-bromobenzoyl)-benzaldehyde

To a stirred solution of 8.2 g. of lithium aluminum hydride in 180 ml.of tetrahydrofuran was added 40 g. of 2-(4-bromobenzoyl)benzoic acid inthe course of 30 minutes. The mixture, after being kept at 25° for 2hours, was cooled and 40 ml. of a saturated sodium sulfate solution wasadded slowly. The mixture was filtered and the filtrate concentrated.The resulting oily residue was dissolved in 32 ml. of acetic acid and 96ml. of xylene. This solution was added to a mixture of 17.1 g. ofselenium dioxide in 60 ml. of acetic acid and 120 ml. of xylene andrefluxed for 17 hours. During this time about 22 ml. of an aqueous phasehad collected in a Dean Stark receiver. The solution was filtered,washed with sodium hydroxide and concentrated. Addition of petroleumether gave white prisms melting at 103°-109°. Recrystallization from amixture of ether and petroleum ether raised the melting point to 110°-113°. Ultraviolet inflexion (2-propanol) at 225 mμ (ε = 17,500) andmaximum at 261 mμ (ε = 22,200); infrared absorption (CHCl₃) at 1675cm.sup.⁻¹ and 1705 cm.sup.⁻¹.

Anal. Calcd. for C₁₄ H₉ BrO₂ : C, 58.16; H, 3.14; Found: C, 57.86; H,3.41

EXAMPLE 6 Preparation of 2,3-dihydro-5-phenyl-5H-imidazo[2,1-a]isoindolesulfate from 2-benzoylbenzaldehyde

A solution of 21 g. of o-benzoylbenzaldehyde in 250 ml. of toluene and34 ml. of ethylenediamine was refluxed for 24 hours. During this time11.5 ml. of an aqueous phase was separated in a Dean Stark receiver. Thereaction mixture was concentrated in vacuo to an orange oil which wasdissolved in ethyl acetate and washed twice with water. The solution wasdried and concentrated, dissolved in 200 ml. of ethyl acetate and asolution of 5.3 ml. of concentrated sulfuric acid in 100 ml. of ethanolwas added. A crystalline precipitate was collected which afterrecrystallization from a mixture of methanol and ethyl acetate gavewhite prisms melting at 226°-229° dec. Ultraviolet maxima (2-propanol)at 240 mμ (ε = 15,000) and 276 mμ (ε = 5,400); infrared absorption (KBr)1660 cm.sup.⁻¹.

Anal. Calcd. for C₁₆ H₁₄ N₂.sup.. H₂ SO₄ : C, 57.82; H, 4.85; N, 8.43;Found: C, 57.61; H, 4.81; N, 8.73

The hydrochloride of 2,3-dihydro-5-phenyl-5H-imidazo[2,1-a]isoindole wasprepared from the corresponding base with aqueous 1 N hydrochloric acid.On recrystallization from a mixture of methanol and toluene, whiteprisms melting at 226°-228° dec. were obtained. Nmr peaks (DMSO) at δ3.6-4.6 (4H, multiplet), at δ 6.13 (1H, singlet), at δ 7.3-7.9 (9H,multiplet).

EXAMPLE 7 Preparation of 2,3-dihydro-5-phenyl-5H-imidazo[2,1-a]isoindolesulfate from 2-(2-aminoethyl)-3-phenylphthalimidine

A solution of 1.2 ml. of titanium tetrachloride in 30 ml. of xylene wasadded at 25° to a stirred solution of 2.5 g. of2-(2-aminoethyl)-3-phenylphthalimidine in 150 ml. of xylene. The mixturewas refluxed for 18 hours, cooled and washed with an aqueous solution ofsodium carbonate. The xylene solution was extracted with 2N hydrochloricacid. The acidic extract was poured on ice and made alkaline with sodiumhydroxide. The solution was extracted with ethyl acetate and the extractwas concentrated. Addition of a solution of sulfuric acid in a mixtureof ethanol and tetrahydrofuran and further dilution with ethyl acetategave a crystalline precipitate. Recrystallization from a mixture ofmethanol and ethyl acetate gave the product as white prisms melting at225°-228° dec.

EXAMPLE 8 Preparation of2,3-dihydro-5-hydroperoxy-5-phenyl-5H-imidazo[2,1-a]isoindole

The base liberated from 16.6 g. of2,3-dihydro-5-phenyl-5H-imidazo[2,1-a]isoindole sulfate was dissolved in50 ml. of ethanol and 11 ml. of a 30 percent by weight aqueous solutionof hydrogen peroxide was added. The mixture was stirred at 25° for 40hours. A crystalline crop was collected and placed on a columncontaining 250 g. of silica gel. Elution with a mixture of 1 part ofmethanol (volume) and 1 part of chloroform (volume) gave fractions fromwhich on concentration a crystalline residue was obtained.Recrystallization from a mixture of methanol and chloroform gave theproduct as white prisms melting at 167°-168° dec. Ultraviolet inflexions(2-propanol) at 232 mμ (ε = 14,000) and 290 mμ (ε = 2600), maxima at 269mμ (ε = 4000) and 275 mμ (ε = 4400), infrared absorption (KBr) at 1665cm.sup.⁻¹.

Anal. Calcd. for C₁₆ H₁₄ N₂ O₂ : C, 72.16; H, 5.30; N, 10.52; Found: C,72.09; H, 5.39; N, 10.22

The hydrochloride of2,3-dihydro-5-hydroperoxy-5-phenyl-5H-imidazo[2,1-a]isoindole wasprepared with methanolic hydrogen chloride and after recrystallizationfrom a mixture of methanol and ether gave white platelets melting at158°-159° dec. Ultraviolet maxima (2-propanol) at 245 mμ (ε = 14,800)and 278 mμ (ε = 5200); infrared absorption (KBr) at 1680 cm.sup.⁻¹.

Anal. Calcd. for C₁₆ H₁₄ N₂ O₂.sup.. HCl: C, 63.47; H, 4.99; Cl, 11.71;Found: C, 63.63; H, 4.83; Cl, 11.79

EXAMPLE 9 Preparation of5-(p-chlorophenyl)-2,3-dihydro-5-hydroperoxy-5H-imidazo[2,1-a]isoindolehydrochloride

1 Gram of 2-(p-chlorobenzoyl)-benzaldehyde was thoroughly mixed with 0.9g. of ethylenediamine toluene sulfonate and heated in a metal bath (bathtemperature, 120°-125°) for 1 minute. On cooling a deep yellow glassymaterial was obtained which on addition of methylene chloride, ethylacetate and petroleum ether gave a crystalline precipitate which wastreated with ice cold aqueous sodium hydroxide. The mixture wasextracted with ether and the extract was exposed to air at 25° for 18hours. A crystalline crop was collected and suspended in methylenechloride. Addition of ethereal hydrogen chloride gave a crystallinematerial which after recrystallization from a mixture of methanol andether gave white prisms melting at 175°-177° dec. Ultraviolet inflexion(2-propanol) at 223 mμ (ε = 21,800) and 279 mμ (ε = 5600), maximum at243 mμ (ε = 15,500); infrared absorption (KBr) at 1670 cm.sup.⁻¹.

Anal. Calcd. for C₁₆ H₁₃ ClN₂ O₂.sup.. HCl: C, 56.99; H, 4.18; Cl,21.03; N, 8.31; Found: C, 57.14; H, 4.15; Cl, 21.02; N, 8.30

EXAMPLE 10 Preparation of 2-(2-benzoylphenyl)-2-imidazoline from2,3-dihydro5-phenyl-5H-imidazo[2,1-a]isoindole

To a suspension of 8.5 g. of2,3-dihydro-5-phenyl-5H-imidazo[2,1-a]isoindole sulfate in water wasadded 50 ml. of 1N aqueous sodium hydroxide. Extraction with methylenechloride and concentration gave an orange oil which was dissolved in amixture of 30 ml. of methylene chloride and 30 ml. of ethanol. To thissolution was added 2.3 ml. of 30 percent by weight hydrogen peroxide.After stirring at 25° for 18 hours, a precipitate was collected whichafter recrystallization from methanol gave white prisms melting at194°-196° dec. Ultraviolet inflexions (2-propanol) at 225 mμ (ε =15,500) and 290 mμ (ε = 2250), maxima at 269 mμ (ε = 4100) and 276 mμ (ε= 4250); infrared absorption (KBr) 1660 cm.sup.⁻¹.

Anal. Calcd. for C₁₆ H₁₄ N₂ O: C, 76.78; H, 5.64; N, 11.19; Found: C,76.42; H, 5.79; N, 11.13

The 2-(2-benzoylphenyl)-2-imidazoline prepared in this manner can formthe isomeric 2,3-dihydro-5-hydroxy-5-phenyl-5H-imidazo[2,1-a]isoindole.

The hydrochloride was prepared by adding a solution of hydrogen chloridein methanol to a suspension of 2-(2-benzoylphenyl)-2-imidazoline inmethanol. Ether was added and the crystalline precipitate was collected.Recrystallization from a mixture of methanol and ether gave white prismsmelting at 173°-176° dec. Ultraviolet maximum (2-propanol) at 252 mμ (ε= 13,600); infrared absorption (KBr) at 1665 cm.sup.⁻¹.

Anal. Calcd. for C₁₆ H₁₄ N₂ O.sup.. HCl: Cl, 12.36; Found: Cl, 12.22

The hydrobromide was prepared by adding an aqueous solution ofhydrobromic acid to a suspension of 2-(2-benzoylphenyl)-2-imidazoline inethanol. Addition of ether gave a precipitate which afterrecrystallization from a mixture of ethanol and ether gave whiteplatelets melting at 193°-194° dec.

Anal. Calcd. for C₁₆ H₁₄ N₂ O.sup.. HBr: Br, 24.13; Found: Br, 24.15

EXAMPLE 11 Preparation of 2-(2-benzoylphenyl)-2-imidazoline from2,3-dihydro-5-hydroperoxy-5-phenyl-5H-imidazo[2,1-a]isoindole

A solution of 0.7 g. of sodium sulfite heptahydrate in 3 ml. of waterwas added to 0.5 g. of2,3-dihydro-5-hydroperoxy-5-phenyl-5H-imidazo[2,1-a]isoindole in 7 ml.of dimethylformamide. The solution was heated to 100° for 15 minutes. Oncooling and addition of 20 ml. of water,2-(2-benzoylphenyl)-2-imidazoline was obtained.

EXAMPLE 12 Preparation of 2-(2-benzoylphenyl)-2-imidazoline from2,3-dihydro-5-hydroperoxy-5-phenyl-5H-imidazo[2,1-a]isoindole

A solution of 0.1 g. of2,3-dihydro-5-hydroperoxy-5-phenyl-5H-imidazo[2,1-a]isoindole and 0.33g. of triethylphosphite in 20 ml. of ethanol was kept on a steam bathfor 5 minutes, then 18 hours at 25°. The solution was concentrated invacuo and on addition of water 2-(2-benzoylphenyl)-2-imidazoline wasobtained.

EXAMPLE 13 Preparation of 2-(2-benzoylphenyl)-2-imidazoline from2-(2-aminoethyl)-1-phenylisoindoline

A solution of 3.3 g. of chromium trioxide and 5.9 g. of2-(2-aminoethyl)-1-phenylisoindoline in 250 ml. of acetic acid wasstirred at 55°-60° for 18 hours. The solution was cooled, poured on iceand made alkaline. Extraction with methylene chloride and removal of thesolvent gave a brown oil which partly crystallized. Recrystallizationfrom a mixture of chloroform and ethyl acetate gave the product as whiteprisms melting at 194°-196° dec.

EXAMPLE 14 Preparation of 2-(2-aminoethyl)-1-phenylisoindoline

A solution of 127 g. (0.59 mole) of 2-hydroxymethylbenzhydrol wasdissolved in 900 ml. of benzene, 80 g. of anhydrous magnesium sulfatewas added and the mixture was cooled in an ice bath. Hydrogen bromidewas bubbled into the stirred solution until saturation which took about30 minutes. During this time the temperature of the solution was kept at15°-18°. The ice bath was removed and the temperature was allowed torise to 35° in the course of 1 hour. The mixture was heated for anotherhour at 40°-45° on a steam bath. During the whole time hydrogen bromidewas passed into the solution to keep it saturated. The mixture wasfiltered and the solution was concentrated in vacuo to give a red oilwhich was dissolved in 200 ml. of benzene and added to 342 g. (5.7moles) of ethylenediamine in the course of 15 minutes. During theaddition the mixture was stirred and cooled to maintain a temperature ofca. 40° . The mixture was stirred at 25° for 70 minutes. Two layers wereobtained and separated. The benzene layer was washed with water andconcentrated in vacuo. The residual oil was dissolved in 250 ml. ofether. This solution was extracted twice with 300 ml. of cold 1Nhydrochloric acid. The acidic aqueous phase was made alkaline withaqueous sodium hydroxide and extracted with 350 ml. of ether. Theethereal solution was washed with 250 ml. of water, dried andconcentrated. The residue was an amber oil which crystallized onscratching. This material melted up to ca. 45°.

By analogy there were also prepared the following:

2-(3-aminopropyl)-1-phenylisoindoline

2-(2-aminoethyl)-6-chloro-1-phenylisoindoline

2-(2-aminoethyl)-1-(p-methoxyphenyl)isoindoline

2-(4-aminobutyl)-1-phenylisoindoline

2-(2-amino-2-methylpropyl)-1-phenylisoindoline

2-(2-aminopropyl)-1-phenylisoindoline2-(2-aminoethyl)-1-(p-hydroxyphenyl)isoindoline.

EXAMPLE 15 Preparation of 2-[2'-(4-chlorobenzoyl)phenyl]-2-imidazoline

To 1 ml. of ethylenediamine was added 1 g. of2-(p-chlorobenzoyl)-benzaldehyde in small portions. An exothermicreaction took place and after 5 minutes the reaction mixture was pouredinto ice water. A yellow solid precipitate was collected and dissolvedin methylene chloride. Ether and petroleum ether were added and thesolution was shaken in air at 25°. A crystalline precipitate wasobtained which after recrystallization from a mixture of methylenechloride and methanol gave white needles melting at 178°-180° dec.Ultraviolet maxima (2-propanol) at 223 mμ (ε = 21,250), 268 mμ (ε =4300), 275 mμ (ε = 4320), inflexion at 290 mμ (ε = 2200); infraredabsorption (KBr) at 1660 cm.sup.⁻¹.

Anal. Calcd. for C₁₆ H₁₃ ClN₂ O: C, 67.49; H, 4.60; Found: C, 67.38; H,4.56

The 2-[2'-(4-chlorobenzoyl)phenyl]-2-imidazoline prepared in this mannercan form the isomeric5-(4-chlorophenyl)-2,3-dihydro-5-hydroxy-5H-imidazo[2,1-a]isoindole.

The hydrochloride was prepared by adding a solution of hydrogen chloridein ether to a suspension of5-(4-chlorophenyl)-2,3-dihydro-5-hydroxy-5H-imidazo[2,1-a]isoindole.After stirring for 30 minutes a crystalline crop was collected andrecrystallized from a mixture of chloroform and ether to give whiteprisms melting at 168°-171° dec. Ultraviolet inflexion (2-propanol) at220 mμ (ε = 22,000), maxima at 252 mμ (ε = 12,900), 266 mμ (ε = 13,000);infrared absorption (KBr) at 1670 cm.sup.⁻¹.

Anal. Calcd. for C₁₆ H₁₃ ClN₂ O.sup.. HCl: Cl, 22.08; Found: Cl, 22.18

EXAMPLE 16 Preparation of 2-[2'-(4-anisoyl)phenyl]-2-imidazoline

To 4 ml. of ethylenediamine was added 2 g. of 2-(p-anisoyl)benzaldehydein small portions. The solution was stirred for 10 minutes, poured intoice water and extracted with methylene chloride. The methylene chloridesolution was concentrated, the residue was dissolved in ethanol and astream of air was passed through the solution for 18 hours. Acrystalline precipitate was collected and after recrystallization from amixture of chloroform and ether gave white prisms melting at 171°-174°dec. Ultraviolet maxima (2-propanol) at 227 mμ (ε = 20,200), 277 mμ (ε =8800), 282 mμ (ε = 8750), inflexion at 292 mμ (ε = 7200); infraredabsorption (KBr) at 1660 cm.sup.⁻¹.

Anal. Calcd. for C₁₇ H₁₆ N₂ O₂ : C, 72.84; H, 5.75; N, 9.99; Found: C,73.07; H, 5.71; N, 9.83

The 2-[2'-(4 -anisoyl)phenyl]-2-imidazoline prepared in this manner canform the isomeric2,3-dihydro-5-hydroxy-5-(4-methoxyphenyl)-5H-imidazo[2,1-a]isoindole.

EXAMPLE 17 Preparation of 2-[4'-chloro-2'-benzoylphenyl]-2-imidazoline

To 2 ml. of ethylenediamine was added 0.9 g. of2-benzoyl-4-chlorobenzaldehyde in small portions. The solution wasstirred for 10 minutes, poured into ice water and the solid yellowprecipitate was collected. This solid was dissolved in ether and shakenin air for 45 minutes. A white precipitate was obtained which afterrecrystallization from a mixture of methylene chloride and methanolmelted at 200°-202° dec. Ultraviolet maxima (2-propanol) at 242 mμ (ε =17,500), 278 mμ (ε = 3800), 286 mμ (ε = 3300), inflexions at 270 mμ (ε =3450), 295 mμ (ε = 2400); infrared absorption (KBr) at 1665 cm.sup.⁻¹.

Anal. Calcd. for C₁₆ H₁₃ ClN₂ O: C, 67.49; H, 4.60; Found: C, 67.42; H,4.90

The 2-[4'-chloro-2'-benzoylphenyl]-2-imidazoline prepared in this mannercan form the isomeric7-chloro-2,3-dihydro-5-hydroxy-5-phenyl-5H-imidazo[2,1-a]isoindole.

EXAMPLE 18 Preparation of 2-[2-(4-bromobenzoyl)phenyl]-2-imidazoline

A solution of 6 g. of 2-(4-bromobenzoyl)-benzaldehyde and 6.6 ml. ofethylenediamine in 50 ml. of toluene was refluxed for 18 hours. Duringthis time 0.5 ml. of an aqueous phase had separated in a Dean Starkreceiver. The mixture was concentrated in vacuo and the residual orangeoil was dissolved in a mixture containing 15 ml. of ethanol, 15 ml. ofmethylene chloride and 1.5 ml. of a 30 percent by weight aqueoussolution of hydrogen peroxide. After stirring at 25° for 18 hours awhite precipitate was collected which after recrystallization frommethanol gave white needles melting at 187°-189° dec. Ultraviolet maxima(2-propanol) at 227 mμ (ε = 22,800), 259 mμ (ε = 4700), 275 mμ (ε =4800), inflexion at 292 mμ (ε = 2300); infrared absorption (KBr) at 1660cm.sup.⁻¹.

Anal. Calcd. for C₁₆ H₁₃ BrN₂ O: C, 58.37; H, 3.98; Found: C, 58.27; H,3.75

The 2-[2-(4-bromobenzoyl)phenyl]-2-imidazoline prepared in this mannercan form the isomeric5-(4-bromophenyl)-2,3-dihydro-5-hydroxy-5H-imidazo[2,1-a]isoindole.

The hydrochloride was prepared by adding ethereal hydrogen chloride to asolution of5-(4-bromophenyl)-2,3-dihydro-5-hydroxy-5H-imidazo[2,1-a]isoindole in amixture of methylene chloride and methanol. The precipitate wasrecrystallized from a mixture of ethanol and ether to give white prismsmelting at 155°-158° dec. Ultraviolet inflexion (2-propanol) at 223 mμ(ε = 20,000), maxima at 251 mμ (ε = 12,200) and 271 mμ (ε = 13,300);infrared absorption (KBr) at 1660 cm.sup.⁻¹.

Anal. Calcd. for C₁₆ H₁₃ BrN₂ O.sup.. HCl: Cl, 9.70; Found: Cl, 9.82

EXAMPLE 19 Preparation of2,3-dihydro-5-methoxy-5-phenyl-5H-imidazo[2,1-a]isoindole hydrochloride

A solution of 5 g. of 2-(2-benzoylphenyl)-2-imidazoline in 50 ml. ofmethanol was refluxed for 18 hours. The solution was concentrated invacuo, dissolved in 20 ml. of methanol and 60 ml. of ether was added.Crystals precipitated and were identified as starting material. Themother liquor was concentrated and the residue was recrystallized from amixture of methanol, methylene chloride and ether to give the product aswhite prisms melting at 139°-141° dec. Ultraviolet maxima (2-propanol)at 244 mμ (ε = 14,400) and 278 mμ (ε = 5100); infrared absorption (KBr)at 1670 cm.sup.⁻¹.

    ______________________________________                                        Anal. Calcd. for C.sub.17 H.sub.16 N.sub.2 O.HCl:                                                    C, 67.83; H, 5.70;                                                            OCH.sub.3, 10.32                                       Found:                 C, 67.84; H, 5.61;                                                            OCH.sub.3, 10.44                                       ______________________________________                                    

The corresponding base was obtained as a colorless oil by liberating itfrom the hydrochloride obtained as above with alkali. Ultravioletinflexions (0.1N KOH) at 230 mμ (ε = 14,600), 290 mμ (ε = 2700), maximaat 269 mμ (ε = 4200) and 275 mμ (ε = 4600).

Infrared absorption (smear) at 1660 cm.sup.⁻¹ and nmr peaks (CDCl₃) at δ= 3.12 (3H, singlet, OCH₃), δ = 2.6-3.5 (2H, multiplet, N-CH₂), δ =4.2-4.5 (2H, multiplet, =N--CH₂), δ = 7.1-8.0 (9H, multiplet, aromaticCH).

EXAMPLE 20 Preparation of2,3,4,6-tetrahydro-6-phenylpyrimido[2,1-a]isoindole sulfate

A solution of 10.5 g. of 2-benzoylbenzaldehyde and 22 ml. ofpropylenediamine in 125 ml. of toluene was refluxed for 18 hours. Duringthis time 4.5 ml. of an aqueous phase had separated in a Dean Starkreceiver. The solution was concentrated in vacuo and the residue wasrecrystallized from a mixture of ethanol and petroleum ether to givewhite prisms melting at 170°-172° dec. Ultraviolet maximum (2-propanol)at 238 mμ (ε = 18,200), inflexions at 246 mμ (ε = 16,000), 265 mμ (ε =5600), 276 mμ (ε = 3400) and 285 mμ (ε = 2100); infrared absorption(KBr) at 1675 cm.sup.⁻¹.

Anal. Calcd. for C₁₇ H₁₆ N₂.sup.. H₂ SO₄ : C, 58.94; H, 5.24; Found: C,58.62; H, 5.49

EXAMPLE 21 Preparation of2,3,4,5-tetrahydro-7-hydroxy-7-phenyl-7H-diazepino[2,1-a]isoindole

A solution of 10.5 g. of 2-benzoylbenzaldehyde and 28.5 ml. of1,4-diaminobutane in 100 ml. of toluene was refluxed for 18 hours.During this time 2.5 ml. of an aqueous phase had separated in a DeanStark receiver. The solution was exposed to air for 60 hours,concentrated and diluted with 300 ml. of carbon tetrachloride. Acrystalline precipitate was obtained which was suspended in 40 ml. ofethanol. A solution of 1.9 g. of oxalic acid in 40 ml. of methanol wasadded and the solution was concentrated and diluted with ether. Theprecipitate was collected and recrystallized from a mixture of methanoland ether to give the oxalic acid salt as white prisms melting at ca.200° dec. This salt was suspended in a mixture of aqueous sodiumcarbonate solution and methylene chloride. The methylene chloridesolution was concentrated and the residue was recrystallized from amixture of chloroform and ether to give the product as white needlesmelting at 216°-220° dec. Ultraviolet maxima (2-propanol) at 258 mμ (ε =5000), 265 mμ (ε = 5100), 273 mμ (ε = 4800), inflexions at 230 mμ (ε =15,000), 290 mμ (ε = 2400); infrared absorption (KBr) at 1650 cm.sup.⁻¹.

Anal. Calcd. for C₁₈ H₁₈ N₂ O: C, 77.67; H, 6.52; O, 5.75; Found: C,77.64; H, 6.75; O, 5.64

EXAMPLE 22 Preparation of 2-(2-aminoethyl)-3-phenylphthalimidine

A solution of 25 g. (0.1 mole) of1,2,3,9b-tetrahydro-9b-phenyl-5H-imidazo[2,1-a]isoindol-5-one in 150 ml.of acetic acid containing 2.5 g. of hydrogen chloride was shaken underone atmosphere of hydrogen at 25° using 0.5 g. of platinum oxide ascatalyst. In the course of 7 hours, 3000 ml. of hydrogen (theory ca.2500 ml.) was absorbed and the rate of uptake had slowed downconsiderably. The solution was poured into ice water, basified withammonia and extracted with methylene chloride. The organic phase wasdried and concentrated. The residue crystallized with ether and afterrecrystallization from a mixture of methylene chloride and petroleumether gave white prisms of 2-(2-aminoethyl)-3-phenylphthalimidinemelting at 90°-93°. γ_(CO) ^(CHCl).sbsp.3 = 1685 cm.sup.⁻¹, λ_(max)^(i-prop) = 247 mμ , ε = 6000, 279 mμ, ε = 1900.

Anal. Calcd. for C₁₆ H₁₆ N₂ O: C, 76.16; H, 6.39; Found: C, 75.81; H,6.32

EXAMPLE 23 Preparation of 2-[2-(2-chlorobenzoyl)phenyl]-2-imidazoline

To 250 ml. of concentrated sulfuric acid was added, with stirring andslight cooling, 37.5 g. (0.545 mole) of sodium nitrite. To this wasadded 120.5 g. (0.50 mole) of 2-(2-aminobenzoyl)benzoic acid at such arate that the temperature of the reaction mixture remained between30°-40°. After the addition was complete the reaction mixture wasstirred for one hour and then poured into one liter of ice and water andfiltered. The filtrate was added rapidly to a stirred solution of 55 g.(0.555 mole) of cuprous chloride, 150 g. of sodium chloride, 250 ml. ofconcentrated hydrochloric acid and 300 ml. of water. The precipitatedgum was extracted with chloroform and the extracts were washed twicewith water, dried over anhydrous sodium sulfate and evaporated undervacuo to leave a red oil which crystallized upon scratching.Recrystallization from 200 ml. of ethyl acetate gave2-(2-chlorobenzoyl)benzoic acid as a pink solid. A sample recrystallizedthree times from ethyl acetate gave colorless prisms, double m.p.112°-116° and 124°-126°.

To a stirred suspension of 22.8 g. (0.60 mole) of lithium aluminumhydride in 700 ml. of dry tetrahydrofuran was added 104 g. (0.40 mole)of 2-(2-chlorobenzoyl)benzoic acid prepared as above in portions keepingthe reaction mixture temperature between 15°-30° with ice cooling. Afterthe addition was complete the reaction mixture was stirred for one hour.Ether (400 ml.) was added followed by the slow addition of 80 ml. ofwater, with ice cooling. The mixture was filtered through a largesintered glass funnel which contained a matting of Celite filter-aid.The filtered solids were washed with tetrahydrofuran and the combinedfiltrates were evaporated under vacuo to a yellow oil which crystallizedupon scratching. The material was recrystallized from 150 ml. ofisopropyl ether to give 2-chloro-2'-hydroxymethylbenzhydrol as aslightly pink solid, m.p. 85°-87°. A sample was recrystallized threetimes from isopropyl ether to give colorless prisms, m.p. 86°-87°.

A 2-liter, 3-necked, round bottomed flask was fitted with a mechanicalstirrer, dropping funnel and a Dean-Stark trap fitted with a condenser.A mixture of 41.7 g. (0.376 mole) of selenium dioxide in 150 ml. ofacetic acid and 300 ml. of xylene was refluxed for 15 minutes. To theboiling mixture was added dropwise during one hour, a solution of 74.4g. (0.3 mole) of 2-chloro-2'-hydroxymethylbenzhydrol prepared as abovein 85 ml. of acetic acid and 250 ml. of xylene. The Dean-Stark trap wascooled during this time to promote separation of an aqueous phase. About60 ml. of the aqueous phase was separated during 5 hours. The reactionmixture was refluxed for a total of 22 hours, cooled and filtered. Thefiltrate was added to 800 ml. of ice and water, made alkaline with 50percent sodium hydroxide and the mixture extracted with 600 ml. ofether. The extracts were washed with water, dried over anhydrous sodiumsulfate and evaporated to yield an orange oil which could not becrystallized. Vapor phase chromatographic analysis showed the presenceof two compounds. 45.4 Grams of the oil, 52.5 g. (0.875 mole) ofethylenediamine and 400 ml. of benzene were refluxed for 5 hours in around bottomed flask equipped with a Dean-Stark trap and a condenser.About 6 ml. of aqueous phase separated in the trap. The reaction mixturewas cooled, washed three times with saturated aqueous salt solution anddried over anhydrous sodium sulfate. Air was then bubbled through thebenzene solution for 15 hours but only a small amount of solidseparated.

The benzene was removed under vacuo and the residue was dissolved in 150ml. of ethanol and 40 ml. (0.350 mole) of 30 percent hydrogen peroxide.After stirring for 3 hours the ethanol was removed under vacuo and 300ml. of benzene was added to the residue. The aqueous phase was separatedand the benzene solution was dried over anhydrous sodium sulfate andevaporated under vacuo to leave a pale yellow oil. Ether (150 ml.) wasadded and a crystalline solid separated. The mixture was filtered togive a pale yellow solid, m.p. 164°-167° dec. The ether filtrate wasstirred at room temperature, exposed to air, for two days. Theprecipitated solid was filtered to give an additional pale yellow solid.Thin layer chromatography of the combined solids showed the presence ofone major component, Rf 0.41, and a minor component, Rf 0.67. The lattercomponent was2,3-dihydro-5-hydroperoxy-5-(o-chlorophenyl)-5H-imidazo[2,1-a]isoindolesince the yellow solid precipitated iodine from a saturated methanolicpotassium iodide solution.

To a suspension of the yellow solid in 60 ml. of refluxing methanol wasadded a solution of 4.28 g. (0.017 mole) of Na₂ SO₃.sup.. 7H₂ O in 30ml. of water over a period of 5 minutes. After refluxing for 15 minuteslonger the reaction mixture was cooled and filtered. The filtered solidwas washed 3 times with 20 ml. of water and dried. Recrystallizationfrom methanol-chloroform gave2-[2-(2-chlorobenzoyl)phenyl]-2-imidazoline as colorless prisms, m.p.180°-181° dec.

Anal. Calcd. for C₁₆ H₁₃ ClN₂ O: C, 67.49; H, 4.60; N, 9.84; Found: C,67.15; H, 4.56; N, 9.66

The 2-[2-(2-chlorobenzoyl)phenyl]-2-imidazoline prepared in this mannercan form the isomeric2,3-dihydro-5-hydroxy-5-(2'-chlorophenyl)-5H-imidazo[2,1-a]isoindole.

To a hot solution of 6.0 g. (21.2 mmoles) of2-[2-(2-chlorobenzoyl)phenyl]-2-imidazoline in 25 ml. of 6 N methanolichydrogen chloride and 35 ml. of methanol was added 200 ml. of ether andthe solution cooled. Filtration gave2-[2-(2-chlorobenzoyl)phenyl]-2-imidazoline hydrochloride, m.p.178°-180° dec. Dilution of the mother liquors with 200 ml. of etherfollowed by cooling and filtering afforded an additional quantity ofhydrochloride. Recrystallization from methanol-ether gave colorlessprisms, m.p. 178°-180° dec.

Anal. Calcd. for C₁₆ H₁₄ Cl₂ N₂ O: Cl, 22.08; Found: Cl, 22.00

EXAMPLE 24 Preparation of 2-(2-benzoylphenyl)-2-imidazoline via1,2,3,9b-tetrahydro-5H-imidazo[2,1-a]isoindol-5-one

A solution of 7.5 g. of phthalaldehydic acid in 30 ml. of ethanol and 34ml. of ethylenediamine was refluxed for 16 hours. The solution wasconcentrated in vacuo and the residue was dissolved in methylenechloride. The solution was washed with water, dried and concentrated.The residue was distilled in a bulb tube at 0.3 mm at a bath temperatureof 150°-180°. A colorless oil was obtained which was dissolved inmethanol and on addition of ethereal hydrogen chloride gave white prismsof 1,2,3,9b-tetrahydro-5H-imidazo[2,1-a]isoindol-5-one hydrochloride,m.p. 222°-224° dec.

The salt obtained in the preceding experiment was treated with aqueouspotassium carbonate solution. Extraction with methylene chloride gave anoil of which 0.9 g. was dissolved in a mixture of 25 ml. of benzene and10 ml. of ether. To this solution was added 5.5 ml. of a 2 N solution ofphenyl lithium in a mixture of benzene and ether (7:3). After stirringat 25° for 1 hour the solution was poured into ice water and extractedwith ethyl acetate. This solution was concentrated and the residue wasexposed to air for 48 hours. On addition of methylene chloride crystalswere obtained which were dissolved in methanol. Addition of etherealhydrochloric acid gave white prisms which after recrystallization from amixture of methanol and ether gave crystals melting at 173°-175° dec.This material was identical with authentic2-(2-benzoylphenyl)-2-imidazoline hydrochloride.

We claim:
 1. A compound of the formula ##SPC11##wherein R₁ and R₃ areeach independently selected from the group consisting of hydrogen andhalogen; and R₇ is lower alkylor a pharmaceutically acceptable acidaddition salt thereof.
 2. The compound according to claim 1 wherein R₁and R₃ are each hydrogen, i.e., the compound2,3-dihydro-5-methoxy-5-phenyl-5H-imidazo[2,1-a]isoindole.